Summary Hypertension is a major public health problem, affecting 1 billion people and contributing to death from heart attacks and strokes, the #1 and #3 causes of death in the US. We have used genetic and genomic approaches to identify genes and pathways that underlie this trait, and have identified renal salt handling as a principal determinant of human blood pressure. This work has unexpectedly identified new layers of physiologic regulation that are involeved in orchestrating the activities of diverse electrolyte flux pathways. These new mechanisms reveal that the kidney explicitly regulates the balance between renal salt reabsorption and K+ secretion via regulated activity of WNK kinases, whose level and activity is regulated by volume depletion. We have recently identified two new genes that play key roles in this pathway- these encode KLHL3 and CUL3, partners in an ubiquitin ligase complex. Mutation of either results in a similar phenotype to that resulting from WNK mutations. We have shown that this ubiquitin ligase targets WNKs for degradation and is regulated by phosphorylation. We are defining the biochemistry of this signaling pathway, its regulation by changes in volume and potassium homeostasis, and will produce new models that recapitulate the human disease, allowing further determination of the mechanisms by which this pathway imparts its effects. As part of this effort, we have made an unexpected discovery that has implications both for hypertension and also for the broader nuclear hormone receptor field. We have identified a novel phoshorylation site in the mineralocorticoid receptor (MR) that regulates the ability of MR to bind ligand. This site is exclusively phosphorylated in renal intercalated cells, and is modulated in opposite directions by volume depletion and hyperkalemia; dephosphorylation by AII signaling is WNK4-dependent and increases expression of electrolyte flux pathways in intercalated cells that increase electroneutral salt reabsorption. We will identify the kinase mediating this phosphorylation and elucidate the responsible signaling pathway. We are making a mouse model with inducible loss of phosphorylation in intercalated cells, which will reveal the role of this pathway in blood pressure and electrolyte homestasis.